TY - JOUR
T1 - Targeting Orthosteric and Allosteric Pockets of Aromatase via Dual-Mode Novel Azole Inhibitors.
AU - Caciolla, Jessica
AU - Spinello, Angelo
AU - Martini, Silvia
AU - Bisi, Alessandra
AU - Zaffaroni, Nadia
AU - Gobbi, Silvia
AU - Magistrato, Alessandra
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Breast cancer (BC) is the most diffused cancer type in women and the second leading cause of death among the female population. Effective strategies to fight estrogen responsive (ER+) BC, which represents 70 rely on estrogen deprivation, via the inhibition of the aromatase enzyme, or the modulation of its cognate estrogen receptor. Current clinical therapies significantly increased patient survival time. Nevertheless, the onset of resistance in metastatic BC patients undergoing prolonged treatments is becoming a current clinical challenge, urgently demanding to devise innovative strategies. In this context, here we designed, synthesized, and performed in vitro inhibitory tests on the aromatase enzyme and distinct ER+/ER- BC cell line types of novel azole bridged xanthones. These compounds are active in the low μM range and behave as dual-mode inhibitors, targeting both the orthosteric and the allosteric sites of the enzyme placed along one access channel. Classical and quantum-classical molecular dynamics simulations of the new compounds, as compared with selected steroidal and nonsteroidal inhibitors, provide a rationale to the observed inhibitory potency and supply the guidelines to boost the activity of inhibitors able to exploit coordination to iron and occupation of the access channel to modulate estrogen production.
AB - Breast cancer (BC) is the most diffused cancer type in women and the second leading cause of death among the female population. Effective strategies to fight estrogen responsive (ER+) BC, which represents 70 rely on estrogen deprivation, via the inhibition of the aromatase enzyme, or the modulation of its cognate estrogen receptor. Current clinical therapies significantly increased patient survival time. Nevertheless, the onset of resistance in metastatic BC patients undergoing prolonged treatments is becoming a current clinical challenge, urgently demanding to devise innovative strategies. In this context, here we designed, synthesized, and performed in vitro inhibitory tests on the aromatase enzyme and distinct ER+/ER- BC cell line types of novel azole bridged xanthones. These compounds are active in the low μM range and behave as dual-mode inhibitors, targeting both the orthosteric and the allosteric sites of the enzyme placed along one access channel. Classical and quantum-classical molecular dynamics simulations of the new compounds, as compared with selected steroidal and nonsteroidal inhibitors, provide a rationale to the observed inhibitory potency and supply the guidelines to boost the activity of inhibitors able to exploit coordination to iron and occupation of the access channel to modulate estrogen production.
U2 - 10.1021/acsmedchemlett.9b00591
DO - 10.1021/acsmedchemlett.9b00591
M3 - Article
VL - 11
SP - 732
EP - 739
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 5
ER -